1. ¹Division of Cancer Biology and Tissue Engineering, Department of Oral and Maxillofacial Pathology, School of Dental Medicine Tufts University, Boston, Massachusetts, USA
2. ²Cell and Molecular Physiology, School of Medicine, Tufts University, Boston, Massachusetts, USA
3. ³German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany

Correspondence: Dr Jonathan A. Garlick, Division of Cancer Biology and Tissue Engineering, School of Dental Medicine, Tufts University, South Cove building, Room 116, 55 Kneeland Street, Boston, Massachusetts 02111, USA. E-mail: jonathan.garlick@tufts.edu; Dr Addy Alt-Holland, E-mail: addy.alt_holland@tufts.edu; Dr Ira M. Herman, Department of Physiology, School of Medicine, Tufts University, Arnold building, 116 Harrison Avenue, Boston, Massachusetts 02111, USA. E-mail: Ira.herman@tufts.edu

Received 14 December 2007; Revised 25 February 2008; Accepted 28 February 2008; Published online 5 June 2008.

Abstract

The link between loss of cell–cell adhesion, the activation of cell migration, and the behavior of intraepithelial (IE) tumor cells during the early stages of skin cancer progression is not well understood. The current study characterized the migratory behavior of a squamous cell carcinoma cell line (HaCaT-II-4) upon E-cadherin suppression in both 2D, monolayer cultures and within human skin equivalents that mimic premalignant disease. The migratory behavior of tumor cells was first analyzed in 3D tissue context by developing a model that mimics transepithelial tumor cell migration. We show that loss of cell adhesion enabled migration of single, IE tumor cells between normal keratinocytes as a prerequisite for stromal invasion. To further understand this migratory behavior, E-cadherin-deficient cells were analyzed in 2D, monolayer cultures and displayed altered cytoarchitecture and enhanced membrane protrusive activity that was associated with circumferential actin organization and induction of the nonmuscle, actin isoform. These features were associated with increased motility and random, individual cell migration in response to scrape-wounding. Thus, loss of E-cadherin-mediated adhesion led to the acquisition of phenotypic properties that augmented cell motility and directed the transition from the precancer to cancer in skin-like tissues.